The present invention relates to new benzenesulphonamide compounds, and to pharmaceutical compositions containing them.
The compounds of the present invention have a novel structure giving them a TXA2 receptor antagonist and 5HT2 serotoninergic receptor antagonist character.
1. Description of the Prior Art
Compounds having a benzenesulphonamide chain have been described in Application EP 864 561 in relation to their NO-yielding character and their thromboxane A2 (TXA2) receptor antagonist character, as well as in Application EP 648 741 solely in relation to their TXA2 receptor antagonist properties or WO 95 06046 as antagonists of receptors of TXA2 and precursors thereof, prostaglandin H2 (PGH2).
2. Background of the Invention
Platelet aggregation and vasospasms play an essential role in the aetiology and development of atherothrombotic cardiovascular diseases. TXA2, an arachidonic acid metabolite, and serotonin (5HT), a neurotransmitter, are both powerful vasoconstrictor agents, and are able to induce or reinforce platelet activation, resulting in the aggregation thereof. The vasoconstrictor and pro-aggregation actions of TXA2 are effected through the intermediary of membrane receptors called TP receptors (Medicinal Research Reviews, 1991, 11, 5, p. 503) while those of serotonin are effected through the intermediary of 5HT1 or 5HT2 receptors (T.I.P.S., 1991, 121, p. 223). Research strategies pursued with the aim of finding agents that block the production and/or activation of TXA2 have led to the development of selective TP receptor antagonists, of TXA2-synthase inhibitors, or of mixed agents that exhibit both properties (Medicinal Research Reviews, ibid., T.I.P.S., 1991, 121, 158). Like TXA2, serotonin acts by stimulating platelets and vascular constriction and its activity is found to be increased in atherothrombotic diseases.
The idea of compounds that oppose both the process that causes thromboxane to become active and the process that causes serotonin to become active is extremely useful for the clinician. Such products have the advantage of offering more complete protection both against the activation of platelets and against vasospasms. It will thus be possible for such products to be used in the treatment of pathologies associated with increased activity of TXA2 and 5-HT especially in the treatment of atherothrombotic cardiovascular diseases, such as myocardial infarction, angina pectoris, cerebral vascular accidents, Raynaud""s disease, and also asthma and bronchospasms, as well as migraine and venous diseases.
The present invention relates to compounds of formula (I): 
wherein:
Ra represents a hydroxy, alkoxy, optionally substituted aryloxy or optionally substituted arylalkyloxy, amino, alkylamino, dialkylamino, optionally substituted arylamino or optionally substituted arylalkylamino group,
A represents:
either a CH group, in which case R1 represents a hydrogen atom or an alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted arylcarbonyl, optionally substituted arylcarbonylalkyl, optionally substituted aryloxy, optionally substituted aryloxyalkyl, optionally substituted arylthio, optionally substituted arylthioalkyl, optionally substituted arylamino, optionally substituted arylalkylamino, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylcarbonyl, optionally substituted heteroarylcarbonylalkyl, optionally substituted heteroaryloxy, optionally substituted heteroaryloxyalkyl, optionally substituted heteroarylthio, optionally substituted heteroarylthioalkyl, optionally substituted heteroarylamino or optionally substituted heteroarylalkylamino group,
or a nitrogen atom, in which case R1 represents a hydrogen atom or an alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted arylcarbonyl, optionally substituted arylcarbonylalkyl, optionally substituted arylsulphonyl, optionally substituted aryloxyalkyl, optionally substituted arylthioalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylcarbonyl, optionally substituted heteroarylcarbonylalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heteroarylsulphonyl or optionally substituted heteroarylthioalkyl group,
or R1xe2x80x94A together represent an oxygen atom or a group 
xe2x80x83wherein R3 and R4, which may be identical or different, each represents a hydrogen atom, an optionally substituted aryl group, an alkyl group or an optionally substituted heteroaryl group,
R2 being a hydrogen atom or an alkyl group,
Rb and Rc, which may be identical or different, each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a hydroxy group or a trihaloalkyl group,
n is an integer of from 2 to 6 inclusive,
m and p are identical or different integers of from 0 to 6 inclusive,
to their enantiomers and diastereoisomers, and also to addition salts thereof with a pharmaceutically acceptable acid or base,
wherein:
the term xe2x80x9calkylxe2x80x9d denotes a linear or branched chain having from 1 to 6 carbon atoms,
the term xe2x80x9calkoxyxe2x80x9d denotes a linear or branched alkyl-oxy group having from 1 to 6 carbon atoms,
the term xe2x80x9ctrihaloalkylxe2x80x9d denotes a carbon chain having from 1 to 3 carbon atoms and from 1 to 3 identical or different halogen atoms,
the term xe2x80x9ccycloalkylxe2x80x9d denotes a saturated cyclic group having from 3 to 8 carbon atoms,
the term xe2x80x9carylxe2x80x9d denotes a phenyl or naphthyl group,
the term xe2x80x9cheteroarylxe2x80x9d denotes an aromatic monocyclic group, or a bicyclic group in which at least one of the rings is aromatic, having from 5 to 11 ring members and from 1 to 5 hetero atoms selected from nitrogen, oxygen and sulphur,
the term xe2x80x9csubstitutedxe2x80x9d relating to aryl, arylcarbonyl, arylcarbonylalkyl, aryloxy, aryloxyalkyl, arylthio, arylthioalkyl, arylamino, arylalkylamino, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylcarbonylalkyl, heteroaryloxy, heteroaryloxyalkyl, heteroarylthio, heteroarylthioalkyl, heteroarylamino, and heteroarylalkylamino, arylsulphonyl, arylsulphonylalkyl, heteroarylsulphonyl and heteroarylsulphonylalkyl, denotes that the groups in question are substituted in the aromatic moiety by one or two identical or different substituents selected from halogen atoms and alkyl groups, alkoxy groups, hydroxy groups, cyano groups, nitro groups, amino groups (optionally substituted by one or two alkyl groups) and groups C(O)Rd, Rd representing a group selected from hydroxy, alkoxy and amino, wherein the heteroaryl and heteroarylalkyl groups may also be substituted by an oxo group in the non-aromatic moiety of the heteroaryl.
Preferred compounds of the invention are those wherein, taken together or separately, the value of the substituent m is 2, the value of n is 2, the value of p is 2, the substituent Ra represents a hydroxy group and the substituent R2 represents a hydrogen atom or a methyl group.
An especially advantageous embodiment of the invention relates to compounds of formula (I) wherein m, n and p are each 2, Ra represents a hydroxy group, R2 represents a hydrogen atom or a methyl group, Rb represents a halogen atom, Rc represents a hydrogen atom, and A represents a nitrogen atom in which case R1 represents a hydrogen atom or an alkyl, cycloalkyl, optionally substituted aryl, optionally substituted arylcarbonyl or optionally substituted heteroaryl group, or A represents a CH group in which case R1 represents a hydrogen atom or an alkyl, cycloalkyl, optionally substituted aryl, optionally substituted arylcarbonyl or optionally substituted heteroaryl group, or R1xe2x80x94A together represent an oxygen atom or a group R3R4Cxe2x95x90C wherein R3 and R4 represent an optionally substituted aryl group.
More especially, preferred compounds of formula (I) are those wherein m, n and p are each 2, Ra represents a hydroxy group, R2 represents a hydrogen atom or a methyl group, Rb represents a halogen atom in the para position of the phenyl ring, Rc represents a hydrogen atom and
either A represents a nitrogen atom, in which case R1 represents a phenyl group optionally substituted by a halogen atom, or a heteroaryl group having 9 ring members that contains one or two hetero atoms selected from nitrogen, oxygen and sulphur and is optionally substituted by a halogen atom
or A represents CH group, in which case R1 represents a phenyl group optionally substituted by a halogen atom, a phenylcarbonyl group optionally substituted by a halogen atom, or a heteroaryl group having 9 ring members that contains one or two hetero atoms selected from nitrogen, oxygen and sulphur and is optionally substituted by a halogen atom,
or R1xe2x80x94A together represent a group R3R4Cxe2x95x90C wherein R3 and R4 each represents a phenyl group optionally substituted by a halogen atom.
Advantageously, the invention relates to compounds of formula (I) wherein the optionally substituted heteroaryl group R1 is a benzisoxazolyl group optionally substituted by a halogen atom, a benzothienyl group optionally substituted by a halogen atom, or a benzisothiazolyl group optionally substituted by a halogen atom.
Amongst the preferred compounds of the invention, 3-[3-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-5-(2-{[(4-chlorophenyl)sulphonyl]amino}ethyl)-1H-indol-1-yl]propanoic acid may be mentioned.
The present invention relates also to a process for the preparation of compounds of formula (I), which is characterised in that there is used as starting material a compound of formula (II): 
wherein R2, Rb, Rc, m and p are as defined for formula (I),
which is halogenated to yield a compound of formula (III): 
wherein R2, Rb, Rc, m and p are as defined for formula (I) and X represents a halogen atom,
the halogen atom of which is replaced by an amino group of formula: 
to yield a compound of formula (IV): 
wherein R1, A, R2, Rb, Rc, m and p are as defined for formula (I),
which is subjected to condensation on the indole nitrogen with acrylonitrile, followed by hydrolysis of the nitrile compound in alkaline medium to yield a compound of formula (I/a), a particular case of formula (I): 
wherein R1, A, R2, Rb, Rc, m and p are as defined for formula (I),
the carboxylic acid function of which is optionally converted by reduction into aldehyde, for reaction with an appropriate phosphorus ylid, and which, after catalytic reduction, yields (I/b), a particular case of formula (I): 
wherein R1, A, R2, Ra, Rb, Rc, m and p are as defined for formula (I) and nxe2x80x2 is an integer of from 4 to 6,
which compounds of formula (I/b) may be subjected to hydrolysis of the ester function in acidic or basic medium, according to the reactive groups in the molecule, to yield a compound of formula (I/c): 
a particular case of the compounds of formula (I) wherein R1, R2, Rb, Rc, m and p are as defined for formula (I) and nxe2x80x2 is an integer of from 4 to 6,
which compounds (I/a), (I/b) and (I/c) constitute the totality of the compounds of formula (I) and:
may, if desired, be purified according to a conventional purification technique,
are optionally separated into their stereoisomers according to a conventional separation technique,
are, if desired, converted into their addition salts with a pharmaceutically acceptable acid or base,
it being understood that, at any point considered appropriate during the course of the process described above, the carboxylic acid function may be esterified or the carboxylic ester function may be hydrolysed to the corresponding acid, which may be converted again to a different ester as required by the synthesis.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), alone or in combination with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers.
Amongst the pharmaceutical compositions according to the invention there may be mentioned more especially those which are suitable for oral, parenteral or nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, etc.
The useful dosage varies in accordance with the age and weight of the patient, the nature and the severity of the disorder and also the administration route, which may be oral, nasal, rectal or parenteral. Generally, the unit dosage ranges from 0.1 mg to 500 mg for a treatment of from 1 to 3 administrations per 24 hours.
The following Examples illustrate the invention and do not limit it in any way. The structures of the described compounds have been confirmed by customary spectroscopic and spectrometric techniques.
The starting materials employed are known products or products prepared according to known procedures.
Step a: N-[2-(4-Aminophenyl)ethyl]-4-chlorobenzenesulphonamide
47.5 ml of triethylamine and then, in portions, 72 g of 4-chlorobenzenesulphonyl chloride, are added at ambient temperature to a solution of 46.5 g (340 mmol) of 4-(2-aminoethyl)aniline in a liter of dichloromethane. The mixture is then stirred for one night and subsequently filtered. The solid obtained is washed with water and dried using a dessicator to yield the expected product.
Step b: 4-Chloro-N-[2-(4-hydrazinophenyl)ethyl]benzenesulphonamide Hydrate
A solution of 11.5 g of sodium nitrite in 40 ml of water is added at xe2x88x9210xc2x0 C. to a suspension of 20 g (64 mmol) of the product described in the above Step in 140 ml of concentrated hydrochloric acid. After stirring for 10 minutes at xe2x88x9210xc2x0 C., a solution of 200 g of tin dichloride in 260 ml of concentrated hydrochloric acid is added. The suspension is stirred for 3 hours at ambient temperature. The solid obtained is filtered off and taken up in 800 ml of methanol. Insoluble material is filtered off and the volume of methanol is reduced by evaporation to a volume of 400 ml. The expected product is isolated by crystallisation.
Step c: 4-Chloro-N-[2-[3-(2-hydroxyethyl)-]H-indol-5-yl]ethylybenzenesulphonamide
A solution of 5.8 ml (45 mmol) of 2-ethoxytetrahydrofuran in 240 ml of ethanol is added at 60xc2x0 C. over a period of 20 minutes to a solution of 15 g (41 mmol) of the product described in the above Step in a mixture of 145 ml of ethanol and 15 ml of water. The mixture is heated at reflux for 4 hours. After removal of the solvent by evaporation and purification on a silica column using a 95/5/0.5 dichloromethane/methanol/ammonium hydroxide mixture as eluant, the title product is obtained
The expected product is obtained according to the procedures described in Preparation A, with the replacement of 2-ethoxytetrahydrofuran with 5-hydroxy-2-pentanone in Step c.
Step a: N-[2-(4-Aminophenyl)ethyl]-4-chlorobenzenesulphonamide
The expected product is obtained according.to the procedure described in Preparation A, Step a.
Step b: N-[2-(4-Amino-3-iodophenyl)ethyl]-4-chlorobenzenesulphonamide
2.08 g of calcium carbonate and 5.56 g of benzyltrimethylammonium dichloroiodate are added at ambient temperature to a solution of 5 g (16 mmol) of the above-synthesised product in 100 ml of methanol and 50 ml of dichloromethane. After stirring for 3 hours, the suspension is filtered and the filtrate is evaporated. The solid obtained is taken up in dichloromethane, and the solution is washed with aqueous 10% sodium bisulphate solution and then with water, and subsequently dried over magnesium sulphate. Evaporation of the solvent yields the expected product.
Step c: 4-Chloro-N-{2-[3-(3-hydroxypropyl)-1H-indol-5-yl]ethyl}benzenesulphonamide
Preparation of trimethylsilyl 5-(trimethylsilyl)-4-pentynyl ether.
300 ml of a solution of 1.6N n-butyllithium in hexane are added at xe2x88x9235xc2x0 C. to a solution of 20 g (237 mmol) of 4-pentyn-1-ol in 250 ml of THF. After stirring for 30 minutes at xe2x88x9220xc2x0 C., 62 ml (486 mmol) of trimethylsilyl chloride are added. After increasing again to ambient temperature and stirring for 2 hours, 600 ml of ether and 600 ml of pentane are added, followed by an aqueous 1% sodium carbonate solution. After decanting, drying the organic phase over magnesium sulphate and removing the solvents by evaporation, the silylated compound is isolated.
There are suspended, in 100 ml of DMF, 5 g (11.5 mmol) of trimethylsilyl 5-(trimethylsilyl)-4-pentynyl ether prepared above, 2.6 g (11.5 mmol) of the product described in Preparation C, Step b, 6 g of sodium carbonate and 100 mg of palladium acetate. The reaction mixture is heated at 110xc2x0 C. for 4 hours. The DMF is then evaporated off and the mixture is taken up in dichloromethane. The organic phase is washed with water and dried over magnesium sulphate and the solvent is evaporated off. The black oil obtained is taken up in 50 ml of ethanol and then treated with 5 ml of 1N hydrochloric acid. After 2 hours at ambient temperature, the ethanol is evaporated off. The oil is taken up in dichloromethane, and the organic phase is washed with water, dried over magnesium sulphate and evaporated to yield the expected product.